Orthotopic whole organ transplantation is expensive and invasive. Moreover, there is an acute shortage of donor organs. Accordingly, cell transplantation has been considered as a potential alternative to whole organ transplantation. Cell transplantation has been around for two decades but has not been clinically very useful because even when primary or stem cells can engraft in organs they often cannot selectively proliferate or repopulate the intended organ. Accordingly, cell transplantation without a preparative regimen of is ineffective because of poor engraftment of the transplanted cells in the host organ. Administration of growth factors alone cannot offer selective proliferative/growth advantage to the transplanted cells over the residual host cells and have not been used clinically.
There is a great clinical need for cell transplantation treatments which can restore an organ to health and provide for its biological functions. For instance, with respect to liver disease, more than 40,000 patients die of terminal liver diseases every year in the United States alone, and it is estimated that approximately 20 million suffer from liver diseases (Hagmann, M., Science, 287:1185, 1187 (2000)). For those with inherited metabolic liver diseases or terminal liver failure, orthotopic liver transplantation (OLT) is the only treatment option, but most die without OLT because of a critical shortage of donor livers. Out of 1.3 million patients who may benefit from OLT, only about 4000 patients receive it each year (Hagmann, M., Science, 287:1185, 1187 (2000)). In theory, many patients with primary or metastatic cancers in the liver could also be cured, or have their survival and/or the quality of life improved, by total hepatectomy with OLT. In practice, however, cancer patients are rarely considered for OLT because of the long waiting lists for donor liver.
In a clinical trial of hepatocyte transplantation (HT), 7.5 billion normal allogeneic hepatocytes (representing ˜5% of the hepatocyte mass) were transplanted in a 10-year old girl with Crigler-Najjar syndrome type 1 (Fox, I. et al., N Engl J Med, 338:1422-1426 (1998)). Although the study demonstrated the long-term safety of HT, only partial correction of the metabolic disorder was achieved, because of the lack of proliferation of the engrafted donor hepatocytes. Similarly, a clinical trial of ex vivo hepatic gene therapy in patients with familial hypercholesterolemia failed to demonstrate convincing therapeutic effect (Raper, S. et al., Ann Surg, 223:116-126 (1996); Grossman, M. et al., Nat Med, 1:1148-1154 (1995)) because only a fraction of the transplanted cells engrafted and those that engrafted failed to proliferate in the host liver.
While it has been established that HT can be employed safely in humans, its applicability remains limited by:                (i) a critical shortage of donor hepatocytes,        (ii) the number of hepatocytes that can be transplanted safely, without causing portal hypertension,        (iii) the inability of the transplanted hepatocytes to proliferate in the host liver, and        (iv) lack of a noninvasive method to evaluate the repopulation of transplanted hepatocytes in the liver.        
New strategies to provide a selective growth advantage to the engrafted cells over the host endogenous cells of the target organ are needed. These strategies can allow the diseased host cells to be replaced progressively with normal ones.